Obesity-induced alterations to the immunoproteasome : a potential link to impaired proteostasis in skeletal muscle.

Effective maintenance of muscle mass is a highly regulated, complex process dependent on a tight balance between muscle protein synthesis and breakdown. Evidence suggests obesity creates a toxic intramuscular environment, which can damage cellular proteins. Such a disruption to proteostasis likely contributes to obese muscle pathology. Although inflammation and/or oxidative stress are considered central to impaired proteostasis, the underlying mechanisms are unclear. Nevertheless, the immunoproteasome (iProt), known to respond to inflammation and oxidative damage, may play a role. The overarching aims of the studies depicted in this body of work were two-fold. The investigation discussed in Chapter Four sought to elucidate whether a high-fat, high-sucrose diet alters intramuscular iProt content and catalytic activity in wild-type mice to identify a possible mechanism for impaired muscle proteostasis in obesity. Total proteasome content and activity, as well as estimates of muscle oxidative damage, inflammation, muscle mass and strength were also assessed. However, the procedure to analyze iProt activity was previously validated on mouse spleen extracts, and the translatability to skeletal muscle was unknown. Consequently, Chapter Three describes a preliminary study to optimize the assay protocol in murine skeletal muscle. The results from Chapter Four demonstrate oxidatively damaged proteins were increased in the muscle of obese mice. These intramuscular alterations also coincided with reduced iProt and total proteasome activity, and reductions in relative muscle mass and strength. Muscle inflammation was unaffected by obesity. Since the proteasome, particularly the iProt, is a prime mediator in the removal of oxidized proteins, our findings suggest proteasome dysfunction could be a key determining event in the loss of intramuscular proteostasis with obesity. As impaired proteostasis diminishes muscle integrity, the inability to contain oxidative protein damage via the proteasome, provides a plausible explanation for the loss of muscle mass and strength noted in the obese mice. Consequently, the results from the study in Chapter Four not only enhance our understanding of proteasome function in obese muscle pathology, but also suggest the proteasome could be a potential therapeutic target to optimize the maintenance of muscle mass and function in obese individuals.